5H-Cyclopenta[h]quinazoline, 6,7,8,9-tetrahydro-7,7,8,9,9-pentamethyl-

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolism and excretion of the substance. Sinfonide is expected to be readily absorbed via the oral, inhalation and dermal route. For route to route extrapolation the final absorption percentages derived are: 50% oral absorption, 100% inhalation absorption and 10% dermal absorption.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Toxico-kinetic information on Sinfonide

Introduction

Sinfonide (CAS# 1315251-11-6) is a mono-constituent substance which is a pyrimidine derivative. Sinfonide has a molecular weight of 242.36 g/mol, and is a solid with a melting point of 70.7 ± 0.5°C, a boiling point of 335 ± 1.0 °C, a water solubility of 3.95 mg/L, a vapour pressure of 0.016 Pa and a log Kow of 5.11.

Absorption

Oral route: In an oral (gavage) repeated dose (OECD 407) and a reproduction/developmental toxicity screening test (OECD 421), systemic effects were observed in exposed animals. The effects on liver, pituitary and thyroid weights, and microscopic findings in the liver and stomach indicate that Sinfonide is absorbed via the oral route. Based on the molecular weight (242.36 g/mol), the high log Kow (5.11) and low water solubility (3.95 mg/L) absorption through the gut is expected. Lipophilic compounds may be absorbed into the lymphatic system in form of micelles. According to Martinez and Amidon (2002) the optimal log Kow for oral absorption falls within a range of 2-7. All this information indicates that Sinfonide is likely to be absorbed orally. The oral absorption is assumed to be 50%.

Dermal route: Based on the partition coefficient (Log Kow 5.11) and molecular weight (242.36 g/mol), the dermal absorption is anticipated to be maximally 10%, according to ECHA R.7.12 guidance. In addition, based on the LD50 values determined in the oral and acute toxicity studies (500 mg/kg bw and > 2000 mg/kg bw, respectively), it could be argued that the dermal absorption is at least 4 times less than the oral absorption. Therefore, the dermal absorption rate is considered to 10%.

Inhalation route: Absorption via the lungs is also indicated based on physico-chemical properties. Though the inhalation exposure route is thought minor, because of its low volatility (0.016 Pa), the octanol/water partition coefficient (Log Kow 5.11), indicates that inhalation absorption is possible. The blood/air (BA) partition coefficient is another partition coefficient indicating lung absorption. Buist et al. 2012 have developed BA model for humans using the most important and readily available parameters:

Log PBA = 6.96 – 1.04 Log (VP) – 0.533 (Log) Kow – 0.00495 MW.

For Sinfonide the B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 Log (0.016) – 0.533 x 5.11 – 0.00495 x 242.36 = 6.96 + 1.868 – 2.724 – 1.2 = 4.9

This means that the substance has a high tendency to go from air into the blood. It should, however, be noted that this regression line is only valid for substances which have a vapour pressure > 100 Pa. Despite Sinfonide being somewhat out of the applicability domain and the exact B/A may not be fully correct, it can be assumed that the substance will be absorbed via the inhalation route and will be close to 100%. An acute inhalation toxicity study (Harlan, 2014) is also available where systemic effects are observed.

Distribution

The log Kow of 5.11 (lipophilic) would suggest that the substance would pass through the biological membranes. Furthermore, the systemic effects of oral administration of Sinfonide, such as liver, pituitary and thyroid weight changes along with macro- and microscopical changes in the liver suggest that the substance is present in these organs after oral exposure.

The high lipophilicy of Sinfonide (log P>4) suggests a potential for the substance to accumulate in the adipose tissue of individuals that are frequently exposed. The predicted metabolism of the substance would limit the accumulation in the body fat and therefore there is no bioaccumulation for air-breathing animals, see below.

Metabolism

There are no experimental data on the metabolism of Sinfonide. The pyrimidine ring with two nitrogens can be protonated under acidic conditions (one nitrogen at the time) such as existing in the stomach deprotonated in the gut. This protonated nitrogen is a fairly strong acid with a pKa of 2.53 and may cause the irritancy in the stomach as seen in the gavage DRF (SPARC calculation attached).

In the liver, the following CYP450-mediated reactions are predicted by ToxTree (v 3.1.0.): aliphatic hydroxylation and N-oxidation (Fig.1). Furthermore, based on the modelling performed by Xenosite UGT v.1 (Dang et al., 2016), the nitrogens are likely to be the sites for UGT-mediated glucuronidation (Fig. 2). Sinfonide is not assumed to form any reactive metabolites based on predictions made with Xenosite Reactivity v.1 (Hughes et al., 2015; 2016)

 

Figure 1. Anticipated phase I (CYP-mediated) metabolism of Sinfonide (ToxTree v 3.1.0).

 

 

Figure 2. Predicted sites of UGT-mediated glucuronidation of Sinfonide (Xenosite UGT v.1)

 

Excretion

Sinfonide is likely to be excreted via the urine in the form of glucuronic acid metabolites. As a glucuronide the substance may also be excreted via bile, and may undergo (some) enterohepatic circulation.

Discussion

The substance is expected to be readily absorbed, orally, via inhalation (although the exposure is expected to be low based on the low vapour pressure), and to less extent via the dermal route based on the human toxicological information and physico-chemical parameters. Sinfonide is absorbed orally and metabolism in the liver is anticipated (see metabolism paragraph). The substance is anticipated to become present in the body upon oral administration based on acute and long-term animal studies available. Due to metabolism it will not accumulate in body fat.

For route to route extrapolation

Oral to dermal extrapolation: There are adequate data via the oral route and the critical toxic effect is related to systemic effects and therefore route to route extrapolation is applicable. The toxicity of the substance will be due to the parent compound but also to its metabolites. The overriding principle will be to avoid situations where the extrapolation of data would underestimate toxicity resulting from human exposure to a chemical by the route to route extrapolation. The toxicity of the dermal route will not be underestimated because absorption will be slower and the compound will also pass the liver. Therefore it will be assumed that the oral absorption is 50%, while the dermal extrapolation was calculated to be maximum of 10% will equal dermal absorption.

Oral to inhalation extrapolation

Though the substance is not a volatile liquid the inhalation exposure will be considered. The substance is not a corrosive for skin and eye and the systemic effect will overrule the effects at the site of contact. In the absence of bioavailability data it is most precautionary that 100% of the inhaled vapour is bioavailable. For the oral absorption 50% has been used for route to route extrapolation to be precautionary for the dermal route. For inhalation absorption 100% will be used for route to route extrapolation, because this will be precautionary for the inhalation route.

Conclusion

The substance is expected to be readily absorbed via the oral and inhalation route and somewhat lower via the dermal route based on toxicity and physico-chemical data. Using the precautionary principle for route to route extrapolation the final absorption percentages derived are: 50% oral absorption, 10% dermal absorption and 100% inhalation absorption.

References

Buist, H.E., Wit-Bos de, L., Bouwman, T., Vaes, W.H.J., 2012, Predicting blood:air partion coefficient using basis physico-chemical properties, Regul. Toxicol. Pharmacol., 62, 23-28.

 

Dang, N. L, Hughes, T. B., Krishnamurthy, V., and Swamidass, S. J. (2016). A Simple Model Predicts UGT-Mediated Metabolism. Bioinformatics, DOI: 10.1093/bioinformatics/btw350

 

Hughes, T. B., Miller, G. P., Swamidass, S. J. (2015). Site of Reactivity Models Predict Molecular Reactivity of Diverse Chemicals with Glutathione. Chemical Research in Toxicology, 28(4), 797-809.

 

Hughes, T. B., Dang, N. L., Miller, G. P., Swamidass, S. J. (2016). Modeling Reactivity to Biological Macromolecules with a Deep Multitask Network. ACS Central Science, DOI: 10.1021/acscentsci.6b00162

Martinez, M.N., and Amidon, G.L., 2002, Mechanistic approach to understanding the factors affecting drug absorption: a review of fundament, J. Clinical Pharmacol., 42, 620-643.

 

SPARC calculation: http://archemcalc.com/sparc-web/calc/popup/CalculationReport, calculated September, 2021

Xenosite metabolic predictor: https://swami.wustl.edu/xenosite/p/ugt.Contact; site visited September 2021.